Palladium-Catalyzed Esterification of Aryl Fluorosulfates with Aryl Formates

An efficient palladium-catalyzed carbonylation of aryl fluorosulfates with aryl formates for the facile synthesis of esters was developed. The cross-coupling reactions proceeded effectively in the presence of a palladium catalyst, phosphine ligand, and triethylamine in DMF to produce the corresponding esters in moderate to good yields. Of note, functionalities or substituents, such as nitro, cyano, methoxycarbonyl, trifluoromethyl, methylsulfonyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, methoxy, N,N-dimethyl, and [1,3]dioxolyl, were well-tolerated in the reactions, which could be kept for late-stage modification. The reactions employing readily available and relatively robust aryl fluorosulfates as coupling electrophiles could potentially serve as an attractive alternative to traditional cross-couplings with the use of aryl halides and pseudohalides as substrates.

Et3N as a base) with almost quantitative yields, and they showed hi the corresponding aryl triflates, mesylates, and tosylates, servin alternative to conventional aryl halides and pseudohalides [48,49].Alt with the use of aryl fluorosulfates as substrates for palladium-cata have been developed, in most cases, dangerous CO gas was empl source [61][62][63][64][65][66].Thus, the development of an alternative method for t aryl fluorosulfate is still highly demanded.In the continuation of our e efficient organic reactions with the use of alternative electrophiles report a palladium-catalyzed carbonylation of aryl fluorosulfate with efficient access to ester (Scheme 1c).

Results
Our investigation began with the optimization of reaction conditi sulfurofluoridate (1a) and phenyl formate (2a) as substrates (Table 1) reaction was performed by employing various transition metal salts presence of 1,3-bis(diphenylphosphino)propane (dppp) and Et3N in h.Among the different catalysts (including Fe(III), Co(II), Mn(III), Pd(II)) screened (entries 1-6), Pd(acac)2 was found to be the catalyst the corresponding ester 3a in 73% NMR yield (entry 6).A subsequ palladium catalysts (entries 7-11) showed that the NMR yield of p slightly improved to 75% by using either Pd2(dba)3 or Pd(OAc)2 as a 11).To further improve the reaction efficiency, a variety of ligands, were investigated by utilizing Pd(OAc)2 as a catalyst (see Tables S1-S Materials for details).It was observed that the use of 4,5-bis(diph dimethylxanthene (XantPhos) to replace dppp as a ligand could product 3a in 82% NMR yield (84% isolated yield, entry 12; also see e Evaluation of reaction temperatures showed that comparable yields c

Results
Our investigation began with the optimization of reaction conditions by using phenyl sulfurofluoridate (1a) and phenyl formate (2a) as substrates (Table 1).Initially, the model reaction was performed by employing various transition metal salts as a catalyst in the presence of 1,3-bis(diphenylphosphino)propane (dppp) and Et 3 N in DMF at 80 • C for 12 h.Among the different catalysts (including Fe(III), Co(II), Mn(III), Cr(III), Ni(II), and Pd(II)) screened (entries 1-6), Pd(acac) 2 was found to be the catalyst of choice, leading to the corresponding ester 3a in 73% NMR yield (entry 6).A subsequent survey of other palladium catalysts (entries 7-11) showed that the NMR yield of product 3a could be slightly improved to 75% by using either Pd 2 (dba) 3 or Pd(OAc) 2 as a catalyst (entries 10-11).To further improve the reaction efficiency, a variety of ligands, bases, and solvents were investigated by utilizing Pd(OAc) 2 as a catalyst (see Tables S1-S3 in the Supporting Materials for details).It was observed that the use of 4,5-bis(diphenylphosphino)-9,9dimethylxanthene (XantPhos) to replace dppp as a ligand could deliver the desired product 3a in 82% NMR yield (84% isolated yield, entry 12; also see entry 13 in Table S1).Evaluation of reaction temperatures showed that comparable yields could be obtained by performing the reactions at 60 • C or 100 • C (entries 13-14), while conducting the reaction at room temperature resulted in considerably eroded efficiency (entry 15).In addition, of the various bases and solvents examined, Et 3 N and DMF were found to be the optimal base and solvent for the present organic transformation (see Tables S2 and S3).Finally, control experiments (entries 16-18) indicated that palladium catalyst, base, and ligand were all essential for the efficient progress of the coupling reactions; without any of them, no expected reaction occurred.With the establishment of the optimal reaction conditions for the coupling reactions (Table 1, entry 12), we proceeded to examine substrate scope of the reaction by employing a range of structurally diverse aryl fluorosulfates.As illustrated in Figure 1, aryl fluorosulfates 1b-n possessing either electron-withdrawing group or electron-donating substituent in the aryl ring efficiently underwent the cross-coupling with phenyl formate (2a) to produce the anticipated ester 3b-n in 24-88% yields.In addition, naphthylsubstituted fluorosulfate 1o worked equally well with 2a under established conditions to give the product 3o in 72% yield.Moreover, fluorosulfate 1p derived from pyridine was proven to be a suitable candidate for the current esterification, providing the desired product 3p in 72% yield.Notably, functional groups or substituents, including nitro, cyano, methylsulfonyl, trifluoromethoxy, fluoro, chloro, t-butyl, phenyl, methyl, methoxy, N,N-dimethyl, and [1,3]dioxolyl, were well-tolerated in the reaction, which could be retained for downstream derivatization.However, when sterically congested 2,6-dimethyl phenyl fluorosulfate was employed as a coupling partner, none of the desired cross-coupled product was obtained, presumably because of the inherent steric hindrance in the substrate.With the establishment of the optimal reaction conditions for the coupling reactions (Table 1, entry 12), we proceeded to examine substrate scope of the reaction by employing a range of structurally diverse aryl fluorosulfates.As illustrated in Figure 1, aryl fluorosulfates 1b-n possessing either electron-withdrawing group or electron-donating substituent in the aryl ring efficiently underwent the cross-coupling with phenyl formate (2a) to produce the anticipated ester 3b-n in 24-88% yields.In addition, naphthyl-substituted fluorosulfate 1o worked equally well with 2a under established conditions to give the product 3o in 72% yield.Moreover, fluorosulfate 1p derived from pyridine was proven to be a suitable candidate for the current esterification, providing the desired product 3p in 72% yield.Notably, functional groups or substituents, including nitro, cyano, methylsulfonyl, trifluoromethoxy, fluoro, chloro, t-butyl, phenyl, methyl, methoxy, N,N-dimethyl, and [1,3]dioxolyl, were well-tolerated in the reaction, which could be retained for downstream derivatization.However, when sterically congested 2,6-dimethyl phenyl fluorosulfate was employed as a coupling partner, none of the desired cross-coupled product was obtained, presumably because of the inherent steric hindrance in the substrate.Next, substrate scope with respect to aryl formates was studied (Figure 2).It wa found that aryl formates 2b-n derived from either an electron-poor or electron-ric phenyl ring were capable of efficiently taking part in the coupling reaction with pheny sulfurofluoridate (1a), leading to the corresponding esters 4b-n in modest to good yield The starting material 1g containing a relatively reactive C-Br bond could be employed a well, albeit generating the desired product 4g in 36% yield.In addition, substrates 2hbearing a methyl group at the ortho, meta, and para position of phenyl ring could react i a similar manner.Likewise, a plethora of functionalities, such as COOMe, CF3, OCF3, F Cl, Br, Me, t Bu, Ph, OMe, and OPh, were well-amenable to the reaction.Moreove naphthyl-and pyrenyl-substituted formates 2o-q made good substrates as wel providing the anticipated esters 4o-q in 78-80% yields.However, when heteroary formate 2r derived from quinoline was subjected to cross-coupling with pheny sulfurofluoridate (1a) under the optimized reaction conditions, none of expected produc 4r was obtained.Next, substrate scope with respect to aryl formates was studied (Figure 2).It was found that aryl formates 2b-n derived from either an electron-poor or electron-rich phenyl ring were capable of efficiently taking part in the coupling reaction with phenyl sulfurofluoridate (1a), leading to the corresponding esters 4b-n in modest to good yields.The starting material 1g containing a relatively reactive C-Br bond could be employed as well, albeit generating the desired product 4g in 36% yield.In addition, substrates 2h-j bearing a methyl group at the ortho, meta, and para position of phenyl ring could react in a similar manner.Likewise, a plethora of functionalities, such as COOMe, CF 3 , OCF 3 , F, Cl, Br, Me, t Bu, Ph, OMe, and OPh, were well-amenable to the reaction.Moreover, naphthyl-and pyrenyl-substituted formates 2o-q made good substrates as well, providing the anticipated esters 4o-q in 78-80% yields.However, when heteroaryl formate 2r derived from quinoline was subjected to cross-coupling with phenyl sulfurofluoridate (1a) under the optimized reaction conditions, none of expected product 4r was obtained.The synthetic utility of the present coupling reaction was further demonstrated in the functionalization of substrates derived from naturally occurring molecules.As shown in Figure 3, the carbonylation could be applied to fluorosulfates 1q-r and/or formate 2s derived from estrone and pterostilbene under the developed conditions, producing the products 3q-r and 4s in 29-92% yields.The synthetic utility of the present coupling reaction was further demonstrated in the functionalization of substrates derived from naturally occurring molecules.As shown in Figure 3, the carbonylation could be applied to fluorosulfates 1q-r and/or formate 2s derived from estrone and pterostilbene under the developed conditions, producing the products 3q-r and 4s in 29-92% yields.The synthetic utility of the present coupling reaction was further demonstrated in the functionalization of substrates derived from naturally occurring molecules.As shown in Figure 3, the carbonylation could be applied to fluorosulfates 1q-r and/or formate 2s derived from estrone and pterostilbene under the developed conditions, producing the products 3q-r and 4s in 29-92% yields.Finally, the current palladium-catalyzed carbonylation of aryl fluorosulfates with aryl formates was found to be amenable to gram-scale synthesis.As shown in Scheme 2, the 6 mmol-scale reaction using 1.06 g of aryl fluorosulfates 1a as substrate proceeded equally well under well-established conditions to give the product 3a in 78% yield.
Molecules 2024, 29, x FOR PEER REVIEW 6 of 17 Finally, the current palladium-catalyzed carbonylation of aryl fluorosulfates with aryl formates was found to be amenable to gram-scale synthesis.As shown in Scheme 2, the 6 mmol-scale reaction using 1.06 g of aryl fluorosulfates 1a as substrate proceeded equally well under well-established conditions to give the product 3a in 78% yield.Based on previous reports [16][17][18][19][20][21][22][23][24][25][26][27][28], a possible reaction mechanism was proposed (Figure 4).Initially, active zero-valent palladium species (LnPd 0 ) A, which is in situ generated in the reaction system, inserts into aryl fluorosulfate 1 to give an arylpalladium(II) intermediate B. On the other hand, carbon monoxide (CO) and phenol (Ar 2 OH) are in situ produced from aryl formate 2 under the action of Et3N.Next, the insertion of CO into organopalladium B gives an acylpalladium(II) species C, which undergoes exchange with phenol (Ar 2 OH) to obtain the corresponding phenoxy(acyl)palladium intermediate D. Finally, a reductive elimination of intermediate D occurs to furnish the desired product 3-4, along with the re-production of palladium species A, which enters the next catalytic cycle.

General Information
Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification.All the aryl fluorosulfates 1 and aryl formates 2 were prepared by following reported method [40,73,80].Analytical thin layer chromatography (TLC) was performed using silica gel plate (0.2 mm thickness).Subsequent to elution, plates were visualized using UV radiation (254 nm).Flash chromatography was performed using Merck silica gel (200-300 mesh) for column chromatography with freshly distilled solvents.IR spectra were recorded on a FT-IR spectrophotometer using KBr optics. 1 H, 13 C, and 19 F NMR spectra were recorded in CDCl3 on Bruker Avance or Jeol 400 MHz spectrometers.Tetramethylsilane (TMS) served as internal standard for 1 H, 13 C and 19 F NMR analysis.High resolution mass spectra (HRMS) were obtained on a Waters Q-TOF Premier Spectrometer (ESI source).Based on previous reports [16][17][18][19][20][21][22][23][24][25][26][27][28], a possible reaction mechanism was proposed (Figure 4).Initially, active zero-valent palladium species (L n Pd 0 ) A, which is in situ generated in the reaction system, inserts into aryl fluorosulfate 1 to give an arylpalladium(II) intermediate B. On the other hand, carbon monoxide (CO) and phenol (Ar 2 OH) are in situ produced from aryl formate 2 under the action of Et 3 N. Next, the insertion of CO into organopalladium B gives an acylpalladium(II) species C, which undergoes exchange with phenol (Ar 2 OH) to obtain the corresponding phenoxy(acyl)palladium intermediate D.
Finally, a reductive elimination of intermediate D occurs to furnish the desired product 3-4, along with the re-production of palladium species A, which enters the next catalytic cycle.
Molecules 2024, 29, x FOR PEER REVIEW 6 of 17 Finally, the current palladium-catalyzed carbonylation of aryl fluorosulfates with aryl formates was found to be amenable to gram-scale synthesis.As shown in Scheme 2, the 6 mmol-scale reaction using 1.06 g of aryl fluorosulfates 1a as substrate proceeded equally well under well-established conditions to give the product 3a in 78% yield.Based on previous reports [16][17][18][19][20][21][22][23][24][25][26][27][28], a possible reaction mechanism was proposed (Figure 4).Initially, active zero-valent palladium species (LnPd 0 ) A, which is in situ generated in the reaction system, inserts into aryl fluorosulfate 1 to give an arylpalladium(II) intermediate B. On the other hand, carbon monoxide (CO) and phenol (Ar 2 OH) are in situ produced from aryl formate 2 under the action of Et3N.Next, the insertion of CO into organopalladium B gives an acylpalladium(II) species C, which undergoes exchange with phenol (Ar 2 OH) to obtain the corresponding phenoxy(acyl)palladium intermediate D. Finally, a reductive elimination of intermediate D occurs to furnish the desired product 3-4, along with the re-production of palladium species A, which enters the next catalytic cycle.

General Information
Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification.All the aryl fluorosulfates 1 and aryl formates 2 were prepared by following reported method [40,73,80].Analytical thin layer chromatography (TLC) was performed using silica gel plate (0.2 mm thickness).Subsequent to elution, plates were visualized using UV radiation (254 nm).Flash chromatography was performed using Merck silica gel (200-300 mesh) for column chromatography with freshly distilled solvents.IR spectra were recorded on a FT-IR spectrophotometer using KBr optics. 1 H, 13 C, and 19 F NMR spectra were recorded in CDCl3 on Bruker Avance or Jeol 400 MHz spectrometers.Tetramethylsilane (TMS) served as internal standard for 1 H, 13 C and 19 F NMR analysis.High resolution mass spectra (HRMS) were obtained on a Waters Q-TOF Premier Spectrometer (ESI source).

General Information
Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification.All the aryl fluorosulfates 1 and aryl formates 2 were prepared by following reported method [40,73,80].Analytical thin layer chromatography (TLC) was performed using silica gel plate (0.2 mm thickness).Subsequent to elution, plates were visualized using UV radiation (254 nm).Flash chromatography was performed using Merck silica gel (200-300 mesh) for column chromatography with freshly distilled solvents.IR spectra were recorded on a FT-IR spectrophotometer using KBr optics. 1 H, 13 C, and 19 F NMR spectra were recorded in CDCl 3 on Bruker Avance or Jeol 400 MHz spectrometers.Tetramethylsilane (TMS) served as internal standard for 1 H, 13 C and 19 F NMR analysis.High resolution mass spectra (HRMS) were obtained on a Waters Q-TOF Premier Spectrometer (ESI source).

General Procedure for the Synthesis of Aryl Fluorosulfates 1a-r
A 500 mL single-neck round-bottom flask was sequentially charged with phenol (100 mmol, 1.0 equiv.),dichloromethane (250 mL, 0.4 M), and triethylamine (42 mL, 300 mmol, 3.0 equiv.), and it was then sealed with a rubber septum.The atmosphere above the solution was removed by gentle vacuum, and SO 2 F 2 gas was subsequently introduced into the flask by a needle from a balloon filled with SO 2 F 2 gas.The reaction mixture was vigorously stirred at room temperature for 12 h.The solvent was evaporated, and the residual was purified by silica gel column chromatography using petroleum ether and EtOAc as eluent to obtain the pure product of aryl fluorosulfate.Spectral data of these compounds are in accordance with those previously documented [73,80].

General Procedure for the Synthesis of Aryl Formates 2a-s
Formic acid (2.3 mL, 60 mmol, 6.0 equiv.) was added to acetic anhydride (3.8 mL, 40 mmol, 4.0 equiv.) at room temperature.The mixture was stirred at 60 • C (oil bath) for 4 h and cooled to room temperature.The resulting solution was transferred to a 100 mL single-neck round-bottom flask containing phenol (10 mmol, 1.0 equiv.)and NaOAc (0.82 g, 10 mmol, 1.0 equiv.).The mixture was stirred at room temperature for 4 h.Then, CH 2 Cl 2 and water was added to the mixture and the organic layer was extracted with CH 2 Cl 2 (60 mL × 3), washed with saturated NaHCO 3 solution and brine, and dried over anhydrous Na 2 SO 4 .The extracts were concentrated under reduced pressure to obtain the crude product, which was further purified through silica gel column chromatography using petroleum ether and EtOAc as eluent to obtain the pure product of aryl formate.Aryl formates 2a-r are known compounds, and their characterization data are in accord with the reported ones [40,47].Aryl formate 2s is a new compound, and its characterization data are shown below.

Conclusions
In summary, an efficient protocol for the easy entry to esters through the palladiumcatalyzed esterification of aryl fluorosulfates with aryl formates was realized.The carbonylative reactions efficiently occurred with the aid of palladium catalyst, phosphine ligand, and triethylamine in DMF to provide the desired esters in modest to high yields with good tolerance to a range of functional groups and substituents embedded in the aryl ring.In addition, the reaction could not only be scaled up with good efficiency, but also be applied to the utilization of substrates derived from naturally occurring estrone and pterostilbene.

Table 1 .
Optimization of reaction conditions by using various catalysts a .

Table 1 .
Optimization of reaction conditions by using various catalysts a .